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MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

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Flower, Michael
Lomeikaite, Vilija
Ciosi, Marc
Cumming, Sarah
Morales Montero, Fernando
Lo, Kitty
Hensman Moss, Davina
Jones, Lesley
Holmans, Peter A.
TRACK-HD Investigators

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Abstract

Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 10 7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

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Huntington’s disease, myotonic dystrophy, transcriptomics, movement disorders, association study

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https://academic.oup.com/brain/article/142/7/1876/5520687

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